Methods of treating subjects having diabetes with chronic kidney disease

ABSTRACT

The present disclosure is directed to a method of treating prediabetes or type 1 or type 2 diabetes mellitus comprising administering to a subject in need thereof an effective amount of imeglimin, wherein the subject has chronic kidney disease.

FIELD OF THE INVENTION

The present invention relates to use of imeglimin for treating metabolicdisorders, such as pre-diabetes, type 1 or type 2 diabetes mellitus, inpatients with renal impairment or chronic kidney disease (CKD).

BACKGROUND

Metabolic disorders affect a patient's normal metabolic process andinclude pre-diabetes and type 1 or type 2 diabetes mellitus. Type 2diabetes mellitus (T2DM) is a long-term metabolic disorder that ischaracterized by high blood sugar, insulin resistance, and relative lackof insulin. The prevalence of type 2 diabetes mellitus is increasingworldwide with approximately 451 million adults affected by diabetes in2017; this number is anticipated to increase to 693 million adults in2045. This global epidemic of diabetes imposes an enormous individual,societal and economic burden, particularly in the presence ofpolyvascular complications of diabetes. Pre-diabetes is the precursorstage before diabetes mellitus in which not all of the symptoms requiredto diagnose diabetes are present, and blood sugar is higher than normalbut not high enough to be called diabetes. Pre-diabetes is associatedwith obesity (especially abdominal or visceral obesity), dyslipidemiawith high triglycerides and/or low HDL cholesterol, and hypertension. Itis thus a metabolic diathesis or syndrome, and it usually involves nosymptoms and only high blood sugar as the sole sign. Type 1 diabetes,once known as juvenile diabetes or insulin-dependent diabetes, is achronic condition in which the pancreas produces little or no insulin.

Chronic kidney disease (CKD) is a condition characterized by a gradualloss of kidney function over time. It is estimated that 30-50% of allpeople with diabetes are affected with chronic kidney disease: more than40% of subjects with CKD also have T2DM. In addition, diabetes is themost frequent underlying cause of CKD and end-stage renal disease(ESRD), with T2DM present in more than 50% of incident ESRD cases. SeeTuttle, et al. Diabetic kidney disease: a report from an ADA ConsensusConference, Diabetes Care. 2014; 37(10): 2864-2883.

Diabetic kidney disease is a chronic progressive disease with limitedtherapeutic options. Standard of care for this population includestherapy with an inhibitor of the renin angiotensin system (RAS) forrenoprotection and diabetes care including management of hyperglycemiaand cardiovascular disease risk factors as it is generally accepted thatthe coincidence of advanced CKD and T2DM presents a greatly acceleratedcardiovascular (CV) risk. Palsson R, Patel UD, Cardiovascularcomplications of diabetic kidney disease, Adv. Chronic. Kidney Dis.2014; 21(3):273-80. In fact, the excess mortality among patients withdiabetes appears to be limited largely to the subgroup with kidneydisease and explained by their high burden of cardiovascular disease.

It is clear that degree of glycemic abnormality predicts development ofnephropathy and sustained, intensive glycemic control protects againstthe development of microvascular complications of diabetes. However, thelong-term impact of intensive glycemic control on clinical outcomes inthe population of patients with coincident T2DM and clinicallysignificant CKD is less clear. Despite the availability of more than 15classes of drugs for managing hyperglycemia in T2DM patients, many ofthese therapies are either not recommended or require significant dosereductions in the presence of concomitant moderate or severe CKD. Thus,there exists a need to develop better treatment options for diabeticpatients with CKD, particularly moderate or severe CKD.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts geometric mean plasma concentrations of imeglimin insubjects with differing degrees of renal impairment, following 1000 mgQD of imeglimin across all days in a Phase 1 study (Linear Scale).

FIG. 2 depicts geometric mean plasma concentrations of imeglimin insubjects with differing degrees of renal impairment, following 1000 mgQD of imeglimin on Day 1 in a Phase 1 study (Semi-Logarithmic Scale).

FIG. 3 depicts geometric mean plasma concentrations of imeglimin insubjects with differing degrees of renal impairment, following 1000 mgQD of imeglimin on Day 8 in a Phase 1 study (Semi-Logarithmic Scale).

FIG. 4 depicts geometric mean plasma concentrations of imeglimin insubjects with normal renal function versus severe renal impairment,following 500) mg bid of imeglimin across all days in a Phase 1 study(Linear Scale).

FIG. 5 depicts placebo-adjusted changes in HbA1c in three dose groups ina Phase 2b study in Japanese T2DM subjects.

FIG. 6 depicts placebo-adjusted changes in HbA1c according to HbA1cbaseline in three dose groups in a Phase 2b study in Japanese T2DMsubjects.

FIGS. 7A and 7B depict percentages of rescue therapy and percentages ofresponders in a Phase 2b study in Japanese T2DM subjects.

FIG. 8 depicts placebo-adjusted decrease in fasting plasma glucose (FPG)in three dose groups in a Phase 2b study in Japanese T2DM subjects.

FIG. 9 depicts boxplots of AUC_(ss24) simulations following imeglimindosing regimens recommended in subjects with various stages of renalfunction.

FIG. 10 depicts predicted daily steady-state exposures (mean and SD) fora Phase 1b study and actual daily steady-state exposures from a previousPhase 2b study.

FIG. 11 depicts day 15 plasma imeglimin maximum concentrations bytreatment and CKD stage. Solid circle=arithmetic mean and X=geometricmean. The box represents the first quartile (Q1), media, and thirdquartile (Q3). The whiskers represent the minimum observation within thelower fence and the maximum observation within the upper fence. Thelower and upper fence is defined as Q1−1.5*(Q3−Q1) and Q3+1.5*(Q3−Q1),respectively.

FIG. 12 depicts day 15 imeglimin area under the plasmaconcentration-time (AUC) profile by treatment and CKD stage. Solidcircle=arithmetic mean and X=geometric mean. The box represents thefirst quartile (Q1), media, and third quartile (Q3). The whiskersrepresent the minimum observation within the lower fence and the maximumobservation within the upper fence. The lower and upper fence is definedas Q1−1.5*(Q3−Q1) and Q3+1.5*(Q3−Q1), respectively.

SUMMARY

The present disclosure provides a method of treating diabetes mellitusin subjects with chronic kidney disease, particularly moderate andsevere CKD, the method comprising orally administering to a subject inneed thereof an effective amount of imeglimin.

DETAILED DESCRIPTION

In order that the present disclosure can be more readily understood,certain terms are first defined. As used in this application, except asotherwise expressly provided herein, each of the following terms shallhave the meaning set forth below. Additional definitions are set forththroughout the application.

In this specification and the appended claims, the singular forms “a.”“an” and “the” include plural referents unless the context clearlydictates otherwise. The terms “a” (or “an”), as well as the terms “oneor more,” and “at least one” can be used interchangeably herein. Incertain aspects, the term “a” or “an” means “single.” In other aspects,the term “a” or “an” includes “two or more” or “multiple.”

Furthermore. “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A. B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C: A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure is related.

The term “about” as used in connection with a numerical value throughoutthe specification and the claims denotes an interval of accuracy,familiar and acceptable to a person skilled in the art. Such interval ofaccuracy is ±10%.

The term “treatment period” means the period of time during which thedrug is administered to a subject and certain parameters of the subjectare measured and compared to the baseline values. For example, thetreatment period can be from about 2 weeks to about 2 years. In someembodiments, the treatment period can be about 2, about 4, about 6,about 8, about 10, about 12, about 14, about 16, about 18, about 20,about 24, about 52, about 76 or about 104 weeks. The efficacy of thedrug can be assessed by measuring certain parameters and calculating thechanges from baseline over the treatment period. The efficacy parametersinclude, but are not limited to, placebo-subtracted decrease inglycosylated hemoglobin (HbA1c) percentage and placebo-subtracteddecrease in fasting plasma glucose (FPG).

The term “AUC” as used herein refers to the area under the curve of aplot of plasma concentration versus time following administration of adrug.

The present disclosure also describes a method of using imeglimin fortreating subjects with pre-diabetes, or diabetes mellitus, and CKD stage3B or stage 4. The present disclosure describes a method of usingimeglimin for treating subjects with T2DM and CKD stage 3B or stage 4.The present disclosure also describes a method of using imeglimin fortreating subjects with type 1 diabetes mellitus and CKD stage 3B orstage 4.

Management of hyperglycemia presents a particular challenge in subjectswith diabetic kidney disease. Because of the loss of renal function inthese subjects, many of the approved classes of anti-hyperglycemictherapies that are renally cleared require reduced doses or are notrecommended. Thus, there are limited therapeutic options for diabetesmanagement in subjects with kidney disease, and particularly moderate orsevere CKD. Insulin and selected insulin secretagogues such assulfonylurea medications are frequently used in this population;however, reduced clearance of insulin prolongs the duration of insulinaction and thereby increases the risk of hypoglycemia events includingsevere hypoglycemia. Taking into consideration the substantialhypoglycemia risk of intensive glycemic control in CKD patients, recentclinical guidelines recommend a target HbA1c of 7.0% in the presence ofmoderate or severe CKD. See American Diabetes Association, Standards ofMedical Care in Diabetes-2018.

Most approved anti-hyperglycemic therapies can be used in patients withan estimated glomerular filtration rate (eGFR) as low as 45 ml/min/1.73m² (i.e., through CKD stage 3A). However, most therapies aredose-reduced or contraindicated in CKD stage 3B and 4 (eGFR 15-44ml/min/1.73 m²) affecting approximately 200,000 incident cases annuallywith nearly two million prevalent cases in the United States. Forexample, metformin is contraindicated in patients with an estimatedglomerular filtration rate (eGFR) below 30 mL/minute/1.73 m², and notrecommended for patients with an eGFR between 30-44 mL/minute/1.73 m².In addition, for many therapeutic agents that can be used in diabeticpatients with CKD, they often lose efficacy as the patients' renalfunction declines. Accordingly, there is a limited set of safe andeffective patient choices for glycemic control for the substantialnumber of patients with this degree of advanced diabetic kidney disease.

Imeglimin is disclosed as5,6-dihydro-4-dimethylamine-2-imino-6-methyl-1,3,5-triazine anddescribed in U.S. Pat. Nos. 7,034,021, 7,452,883, 7,767,676, 7,501,511,8,227,465, 8,791,115, 8,217,040, 8,461,331, 8,846,911, 9,035,048,8,742,102, 8,592,370, 8,980,828, 8,742,103, 9,271,984, and 8,937,066.According to World Health Organization (WHO) criteria, imeglimin can bereferred to as(6R)-N²,N²,6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine. CompoundI is further known as imeglimin.

Imeglimin is the first in a new tetrahydrotriazine-containing class oforal antidiabetic agents, with a unique mechanism of action targetingmitochondria bioenergetics and function.

Imeglimin has been studied in subjects with T2DMs for up to 24 weeks asmonotherapy and as add on to metformin and sitagliptin. In each studyimeglimin was well-tolerated with a safety profile comparable to that ofplacebo and placebo-subtracted reductions in glycosylated hemoglobin(HbA1c) in the range of −0.42% to −0.72% for the dose of 1500 mg twicedaily (BID).

The pharmacokinetics (PK) of imeglimin are characterized by less thandose proportional exposures with increasing dose over the 250 to 2000 mgrange, low protein binding (<8% bound), no appreciable metabolism instandard in vitro assays, and renal elimination as the main excretionpathway.

Methods of Treatment

The present invention relates to a method of using imeglimin in treatingmetabolic disorders in patients with renal impairment or chronic kidneydisease.

In certain embodiments, the patients which may be amenable to the methodof this disclosure may have or are at-risk for one or more of thefollowing diseases, disorders or conditions: type 1 diabetes, type 2diabetes, impaired glucose tolerance (IGT), impaired fasting bloodglucose (IFG), hyperglycemia, postprandial hyperglycemia, fastinghyperglycemia, latent autoimmune diabetes in adults (LADA), overweight,obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, hypertension, atherosclerosis, endothelialdysfunction, osteoporosis, chronic systemic inflammation, nonalcoholicfatty liver disease (NAFLD), polycystic ovarian syndrome, metabolicsyndrome, nephropathy, micro- or macroalbuminuria, proteinuria,retinopathy, cataracts, neuropathy, learning or memory impairment,neurodegenerative or cognitive disorders, cardiovascular diseases,tissue ischaemia, diabetic foot or ulcus, myocardial infarction, acutecoronary syndrome, unstable angina pectoris, stable angina pectoris,peripheral arterial occlusive disease, cardiomyopathy (including e.g.uremic cardiomyopathy), heart failure, cardiac hypertrophy, heart rhythmdisorders, vascular restenosis, stroke, (renal, cardiac, cerebral orhepatic) ischemia/reperfusion injuries. (renal, cardiac, cerebral orhepatic) fibrosis, (renal, cardiac, cerebral or hepatic) vascularremodeling; a diabetic disease, especially type 2 diabetes mellitus(e.g. as underlying disease).

In one aspect, the present disclosure relates to a method of treatingprediabetes or type 1 or type 2 diabetes mellitus comprisingadministering to a subject in need thereof an effective amount ofimeglimin, wherein the subject has chronic kidney disease. It isunexpected that imeglimin provides similar safety and efficacy forpatients with moderate to severe chronic kidney disease compared topatients with normal renal function.

In another aspect, the presented disclosure provides a method ofimproving glycemic control in a subject having prediabetes or type 1 ortype 2 diabetes comprising administering to the subject in need thereofan effective amount of imeglimin, wherein the subject has chronic kidneydisease.

In another aspect, the presented disclosure provides a method ofimproving glycemic control in a subject having prediabetes or type 1 ortype 2 diabetes as an adjunct to diet and exercise, comprisingadministering to the subject in need thereof an effective amount ofimeglimin, wherein the subject has chronic kidney disease.

In some embodiments, the subject has prediabetes. In some embodiments,the subject has type 1 or type 2 diabetes mellitus. In some embodiments,the subject has type 2 diabetes mellitus.

A patient is considered to have chronic kidney disease if they haveabnormalities of kidney function or structure present for more than 3months. The definition of CKD includes all individuals with markers ofkidney damage or those with an estimated Glomerular Filtration Rate(eGFR) of less than 60 ml/min/1.73 m² on at least 2 occasions 90 daysapart (with or without markers of kidney damage). Markers of kidneydisease may include: cystatin-C, albuminuria (albumin-to-creatinineratio (ACR) >3 mg/mmol), haematuria (or presumed or confirmed renalorigin), electrolyte abnormalities due to tubular disorders, renalhistological abnormalities, structural abnormalities detected by imaging(e.g. polycystic kidneys, reflux nephropathy) or a history of kidneytransplantation.

In some embodiments, CKD can be classified based on the patients' eGFR:

Status of Kidney Stages Function eGFR Stage 1 normal kidney function 90or higher Stage 2 mild loss of kidney 60 to 89 function Stage 3A mild tomoderate loss 45 to 59 of kidney function Stage 3B moderate to severeloss 30 to 44 of kidney function Stage 4 severe loss of kidney 15 to 29function Stage 5 End-stage renal disease less than 15 (ESRD)

In some embodiments, the subject has mild renal impairment. In someembodiments, the subject has stage 2 chronic kidney disease.

In some embodiments, the subject has mild to moderate renal impairment.In some embodiments, the subject has moderate to severe renalimpairment. In some embodiments, the subject has stage 3A (or stage 3a)chronic kidney disease. In some embodiments, the subject has stage 3B(or stage 3b) chronic kidney disease. Stage 3A and stage 3B together areconsidered stage 3 chronic kidney disease.

In some embodiments, the subject has severe renal impairment. In someembodiments, the subject has stage 4 chronic kidney disease.

In some embodiments, the subject has stage 3B or stage 4 chronic kidneydisease.

In some embodiments, the subject has an eGFR of from about 45ml/min/1.73 m² to about 59 ml/min/1.73 m².

In some embodiments, the subject has an eGFR of from about 15ml/min/1.73 m² to about 44 ml/min/1.73 m².

In some embodiments, the subject has an eGFR of from about 15ml/min/1.73 m² to about 29 ml/min/1.73 m². In some embodiments, thesubject has an eGFR of from about 30 ml/min/1.73 m² to about 44ml/min/1.73 m².

In some embodiments, the subject has an eGFR of from about 30ml/min/1.73 m² to about 59 ml/min/1.73 m².

In some embodiments, CKD can be classified based on the patients'albumin-to-creatinine ratio (ACR). Albuminuria is increased excretion ofurinary albumin and a marker of kidney damage. Normal individualsexcrete very small amounts of protein in the urine.Albumin-to-creatinine ratio (ACR) is a method to detect elevatedprotein. ACR is calculated by dividing albumin concentration inmilligrams by creatinine concentration in grams. Moderately increasedalbuminuria, known as microalbuminuria (ACR 30-300 mg/g), refers toalbumin excretion above the normal range but below the level ofdetection by tests for total protein. Severely increased albuminuria,known as macroalbuminuria (ACR>300), refers to a higher elevation ofalbumin associated with progressive decline in glomerular filtrationrate.

In some embodiments, the present disclosure provides a method fortreating a subject having a metabolic disorder (e.g., T2DM) and chronickidney disease, the method comprising:

-   -   determining the severity of the subject's chronic kidney        disease;    -   determining an effective dosing regimen of imeglimin for the        subject based on the severity of the chronic kidney disease: and    -   administering imeglimin to the subject according to the dosing        regimen.

In some embodiments, the method comprises orally administering to asubject in need thereof an effective amount of imeglimin. In someembodiments, imeglimin can be administered to a subject via injection,such as intravenous injection.

In some embodiments, the treatment with imeglimin according to themethods described herein is well tolerated.

In some embodiments, an imeglimin-treated subject does not, or a groupof imeglimin-treated subjects do not, experience an increase infrequency of lactic acidosis compared to before the subject or group ofsubjects initiated imeglimin treatment.

In some embodiments, an imeglimin-treated subject does not, or a groupof imeglimin-treated subjects do not, experience an increase orelevation in plasma lactate compared to before the subject or group ofsubjects initiated imeglimin treatment.

In some embodiments, an imeglimin-treated subject does not, or a groupof imeglimin-treated subjects do not, experience an increase orelevation in plasma lactate above a threshold of 3 mmol/L (27 mg/dL)compared to before the subject or group of subjects initiated imeglimintreatment.

In some embodiments, an imeglimin-treated subject is, or a group ofimeglimin-treated subjects are, no more likely or less likely thanplacebo-treated subjects or subjects treated with a secondpharmaceutical agent, including the exemplary anti-diabetic agentsdescribed herein, to experience an increase or elevation in plasmalactate compared to before the subject or group of subjects initiatedimeglimin treatment.

In some embodiments, an imeglimin-treated subject has, or a group ofimeglimin-treated subjects have, a similar or the same frequency oftreatment-emergent adverse events as a placebo-treated subject or groupof subjects.

In some embodiments, the subject or group of imeglimin-treated subjectsaccording to the methods described herein has or have a pre-existingmedical condition. In some embodiments, the pre-existing medicalcondition is not chronic kidney disease.

In some embodiments, an imeglimin-treated subject's or group ofimeglimin-treated subjects' one or more pre-existing conditions does notor do not worsen in severity or symptomatology following treatment withimeglimin compared to that which would be expected if the subject orgroup of subjects took a second pharmaceutical agent, including theexemplary anti-diabetic agents described herein.

In some embodiments, an imeglimin-treated subject does not, or a groupof imeglimin-treated subjects do not, experience an increase in one ormore symptoms of the subject's or subjects' one or more pre-existingmedical conditions compared to before the subject or subjects initiatedimeglimin treatment.

In some embodiments, an imeglimin-treated subject's or group ofimeglimin-treated subjects' one or more pre-existing conditions does notor do not worsen in severity or symptomatology following treatment withimeglimin. In some embodiments, the imeglimin-treated subject's or groupof subjects' one or more pre-existing conditions does or do not worsenin severity or symptomatology following treatment with imeglimincompared to before the subject or subjects initiated imeglimintreatment.

In some embodiments, the pre-existing medical condition is selected fromhyperkalaemia, hypertension, cardiac disorders, gastrointestinaldisorders, nervous system disorders, blood and lymphatic systemdisorders (such as anemia), eye disorders, endocrine disorders, orcombinations thereof.

In some embodiments, the pre-existing medical condition is a cardiacdisorder. In some embodiments, the cardiac disorders are selected fromcoronary artery disease, atrial fibrillation, congestive cardiacfailure, myocardial infarction, or combinations thereof.

In some embodiments, the pre-existing medical condition is agastrointestinal disorder. In some embodiments, the gastrointestinaldisorders are selected from abdominal pain, constipation, diarrhea,flatulence, gastroesophageal reflux, indigestion, nausea/vomiting, orcombinations thereof.

In some embodiments, the pre-existing medical condition is a nervoussystem disorder. In some embodiments, the nervous system disorders areselected from diabetic neuropathy, peripheral neuropathy, orcombinations thereof.

In some embodiments, the pre-existing medical condition is a blood andlymphatic system disorder. In some embodiments, the blood and lymphaticsystem disorders are selected from anemia, pernicious anemia, vitaminB12-dependent anemia, vitamin B12 deficiency, or combinations thereof.

In some embodiments, the pre-existing medical condition is an eyedisorder. In some embodiments, the eye disorders are selected fromglaucoma, cataract, or combinations thereof.

In some embodiments, the pre-existing medical condition is an endocrineor metabolism disorder. In some embodiments, the endocrine or metabolismdisorders are selected from diabetes, gout, hyperuricemia, increasedurate, secondary hypoparathyroidism, or combinations thereof.

In some embodiments, the amount of imeglimin administered per day isfrom about 500 mg to 3000 mg. In some embodiments the amount ofimeglimin administered per day is from about 750 mg to about 3000 mg,from about 1000 mg to about 3000 mg, from about 1250 mg to about 3000mg, from about 1500 mg to about 3000 mg, from about 1750 mg to about3000 mg, from about 2000 mg to about 3000 mg, from about 2250 mg toabout 3000 mg, from about 2500 mg to about 3000 mg, or from about 2750mg to about 3000 mg.

In some embodiments, the amount of imeglimin administered per day isfrom about 500 mg to 2750 mg, from about 500 mg to about 2500 mg, fromabout 500 mg to about 2250 mg, from about 500 mg to about 2000 mg, fromabout 500 mg to about 1750 mg, from about 500 mg to about 1500 mg, fromabout 500 mg to about 1250 mg, from about 500 g to about 1000 mg, orfrom about 500 mg to about 750 mg.

In some embodiments, the amount of imeglimin administered per day isabout 500 mg, about 550 mg, about 600 mg, about 650 mg, about 675 mg,about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,about 825 mg, about 850 mg, about 900 mg, about 1000 mg, about 1100 mg,about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg,about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 300mg, or in a range between any two of the preceding values.

In some embodiments, the amount of imeglimin administered per day isfrom about 500 mg to about 750 mg, from about 750 mg to about 1250 mg,from about 900 mg to about 1100 mg, from about 1000 mg to about 2000 mg,from about 1250 mg to about 1750 mg, or from about 1400 to about 1600mg.

In some embodiments, the amount of imeglimin administered per day isabout 1000 mg. In some embodiment, the amount of imeglimin administeredper day is about 1500 mg. In some embodiments, the amount of imegliminadministered per day is about 2000 mg. In some embodiments, the amountof imeglimin administered per day is 1000 mg. In some embodiments, theamount of imeglimin is administered per day is 1500 mg. In someembodiments, the amount of imeglimin administered per day is 2000 mg.

In some embodiments, the amount of imeglimin administered to a diabeticsubject with CKD per day can be substantially the same as the amountadministered to a diabetic subject with normal kidney function.

In some embodiments, the amount of imeglimin administered to a diabeticsubject with CKD per day is lower than the amount administered to adiabetic subject with normal kidney function.

In some embodiments, the amount of imeglimin administered to a diabeticsubject with CKD (e.g., stage 3B CKD or stage 4 CKD) per day is about20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,about 90%, or about 100% of the amount administered to a diabeticsubject with normal kidney function, or in a range between any twopreceding values, for example, from about 200/o to about 100% of theamount administered to a diabetic subject with normal kidney function.

In some embodiments, the amount of imeglimin administered to a diabeticsubject with CKD (e.g., stage 3B CKD or stage 4 CKD) per day is fromabout 20% to about 40%, from about 20% to about 30%, from about 30% toabout 50%, from about 30% to about 40%, from about 40% to about 60%,from about 40% to about 50%/c, from about 50% to about 70%, from about50% to about 60%, or from about 60% to about 70% of the amountadministered to a diabetic subject with normal kidney function.

In some embodiments, the amount of imeglimin administered to a diabeticsubject with CKD (e.g., stage 3B CKD or stage 4 CKD) per day is about750 mg, about 1000 mg, about 1500 mg, about 2000 mg, or in a rangebetween any two preceding values.

In some embodiments, imeglimin is administered without a meal or beforea meal. In some embodiments, imeglimin is administered more than twohours before a meal. In some embodiments imeglimin is administered witha meal. In some embodiments imeglimin is administered more than twohours after a meal.

In some embodiments, imeglimin is administered once per day, twice perday, or three times per day. In some embodiments, imeglimin isadministered once per day. In some embodiments imeglimin is administeredtwice per day.

In some embodiments, imeglimin is administered to a subject about 500 mgtwice a day. In some embodiments, imeglimin is administered to a subjectabout 750 mg twice a day. In some embodiments, imeglimin is administeredto a subject about 1000 mg twice a day. In some embodiments, imegliminis administered to a subject about 1500 mg twice a day.

In some embodiments, imeglimin is administered to a subject about 750 mgonce a day. In some embodiments, imeglimin is administered to a subjectabout 1000 mg once a day. In some embodiments, imeglimin is administeredto a subject about 1500 mg once a day.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a human or an animal. In some embodiments, the subject is ahuman.

In some embodiments, the subject is a male. In some embodiments, thesubject is a female.

In some embodiments, the subject is over the age of about 18 years. Insome embodiments, the subject is under the age of about 18 years. Insome embodiments, the subject is between about 6 to about 18 years,about 6 to about 12 years, or about 12 to about 18 years. In someembodiments, the subject is over the age of about 20 years. In someembodiments the subject is over the age of about 25 years. In someembodiments, the subject is over the age of about 30 years. In someembodiments, the subject is over the age of about 35 years. In someembodiments, the subject is over the age of 40 years. In someembodiments, the subject is over the age of 45 years. In someembodiments, the subject is over the age of 50 years. In someembodiments, the subject is over the age of 55 years. In someembodiments, the subject is over the age of 60 years. In someembodiments, the subject is over the age of 65 years. In someembodiments, the subject is over the age of 70 years. In someembodiments, the subject is over the age of 75 years.

In some embodiments, imeglimin is administered in the form of a freebase or a pharmaceutically acceptable salt thereof. In some embodiments,imeglimin is administered in the form of a free base. In someembodiments, imeglimin is administered in the form of a pharmaceuticallyacceptable salt thereof. When imeglimin is in a form of apharmaceutically acceptable salt, the salt can include salts withinorganic acid, salts with organic acid, and salts with acidic aminoacid. Useful examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, andphosphoric acid.

Useful examples of the salt with organic acid include salts with formicacid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

In some embodiments, imeglimin is administered in the form of ahydrochloride salt. As described herein, the amount of the imegliminadministered to a subject refers to the amount of the imeglimin freebase. The examples described herein may refer to “imeglimin” whenimeglimin hydrochloride was used.

In some embodiments, the subject has a baseline glycosylated hemoglobin(HbA1c) percentage of from about 6.8% to about 12.0%.

In some embodiments, the subject has a baseline glycosylated hemoglobin(HbA1c) percentage of about 7.0%, about 8.0%, about 9.0%, about 10.0%,about 11.0%, or about 12.0%, or in a range between any two of thepreceding values.

Efficacy of imeglimin can be assessed by measuring the change in certainparameters for the subject over a treatment period. Placebo-subtractedchange or placebo-adjusted change from baseline refers to the differencebetween the change for subjects receiving imeglimin and the change forsubjects receiving placebo. In some embodiments, the change frombaseline is calculated using Lease Squares Means (LS Means).

The primary evaluation of efficacy of imeglimin is based on the level ofglycosylated hemoglobin (HbA1c). The main criteria are the change inHbA1c from baseline to the end of treatment period compared to placebo.

In some embodiments, the subject experiences a placebo-subtracteddecrease in glycosylated hemoglobin (HbA1c) percentage over a treatmentperiod. In some embodiments, the placebo-subtracted decrease in HbA1cpercentage over a treatment period is from about −0.5% to about −1.2%.In some embodiments, the placebo-subtracted decrease in HbA1c percentageover a treatment period is from about −0.6% to about −1.1%, from about−0.7% to about −1.0%, or from about −0.8% to about −0.9%.

In some embodiments, the placebo-subtracted decrease in HbA1c percentageover a treatment period is about −0.5%, about −0.6%, about −0.7%, about−0.8%, about −0.9%, about −1.0%, about −1.1% or about −1.2%, or in arange between any two of the preceding values. In some embodiments, theplacebo-subtracted decrease in HbA1c percentage over a treatment periodis about −0.8%. In some embodiments, the placebo-subtracted decrease inHbA1c percentage over a treatment period is about −1.0%.

In some embodiments, the subject experiences a placebo-subtracteddecrease in fasting plasma glucose (FPG). In some embodiments, theplacebo-subtracted decrease in FPG over a treatment period is from about−20 mg/dL to about −30 mg/dL. In some embodiments, theplacebo-subtracted decrease in FPG over a treatment period is from about−21 mg/dL to about −28 mg/dL, from about −22 mg/dL to about −27 mg/dL,from about −23 mg/dL to about −26 mg/dL, or from about −24 mg/dL toabout −25 mg/dL.

In some embodiments the placebo-subtracted decrease in FPG over atreatment period is about −20 mg/dL, about −21 mg/dL, about −22 mg/dL,about −23 mg/dL, about −24 mg/dL, about −25 mg/dL, about −26 mg/dL,about −27 mg/dL, about −28 mg/dL, about −29 mg/dL, or about −30 mg/dL,or in a range between any two of the preceding values. In someembodiments the placebo-subtracted decrease in fasting plasma glucoseover a treatment period is about −25 mg/dL.

In some embodiments, the subject has daily steady-state exposures ofimeglimin (AUC_(24,ss)) of from about 10 μg·hr/mL to about 100 μg·hr/mL.In some embodiments, the subject has daily steady-state exposures ofimeglimin (AUC_(24,ss)) of about 10 μg·hr/mL, about 15 μg·hr/mL, about20 μg·hr/mL, about 25 μg·hr/mL, about 30 μg·hr/mL, about 35 μg·hr/mL,about 40 μg·hr/mL, about 45 μg hr/mL, about 50 μg·hr/mL, about 55μg·hr/mL, about 60 μg·hr/mL, about 65 μg·hr/mL, about 70 μg·hr/mL, about75 μg hr/mL, about 80 μg·hr/mL, about 90 μg·hr/mL, about 100 μg·hr/mL,or in a range between any two of the preceding values.

In some embodiments, the subject has daily steady-state exposures ofimeglimin (AUC_(24,ss)) of from about 10 μg·hr/mL to about 50 μg·hr/mL,from about 10 μg·hr/mL to about 40 μg·hr/mL, from about 10 μg·hr/mL toabout 30 μg·hr/mL, or from about 10 μg·hr/mL to about 20 μg·hr/mL. Insome embodiments, the subject has daily steady-state exposures ofimeglimin (AUC_(24,ss)) of from about 20 μg·hr/mL to about 80 μg·hr/mL,from about 20 μg·hr/mL to about 70 μg·hr/mL, from about 20 μg·hr/mL toabout 60 μg hr/mL, from about 20 μg·hr/mL to about 50 μg hr/mL, fromabout 20 μg·hr/mL to about 40 μg·hr/mL, or from about 20 μg·hr/mL toabout 30 μg·hr/mL.

In some embodiments, the subject has received prior anti-diabetictreatment, for example, treatment for type 2 diabetes mellitus.

Prior treatment can be suitable anti-diabetic agents, including but notlimited to, an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, aphosphodiesterase (PDE)-10 inhibitor, a diacylglycerol acyltransferase(DGAT) 1 or 2 inhibitor, a sulfonylurea (e.g., acetohexamide,chlorpropamide, diabinese, glibenclamide, glipizide, glyburide,glimepiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor(e.g., tendamistat, trestatin and AL-3688), an α-glucoside hydrolaseinhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine,camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, andsalbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone andtroglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g.,exendin-3 and exendin-4), a protein tyrosine phosphatase-1B (PTP-1B)inhibitor (e.g., trodusquemine, hyrtiosal extract, and compoundsdisclosed by Zhang, S., et al., Drug Discovery Today, 12(9/10), 373-381(2007)), SIRT-1 inhibitor (e.g., reservatrol), a dipeptidyl peptideaseIV (DPP-IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin andsaxagliptin), an insulin secreatagogue, a fatty acid oxidationinhibitor, an A2 antagonist, a c-jun amino-terminal kinase (INK)inhibitor, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor, a VPAC2 receptor agonist, a glucokinase activator, and asodium glucose transporter (SGLT2 or SGLT1/2) inhibitor.

In some embodiments, the subject has not received prior anti-diabetictreatment, for example, treatment for type 2 diabetes mellitus.

In some embodiments, imeglimin is administered with a secondpharmaceutical agent. In some embodiments, imeglimin is administeredconcomitantly with the second pharmaceutical agent. In some embodiments,imeglimin is administered sequentially with the second pharmaceuticalagent.

In some embodiments the second pharmaceutical agent is selected from thegroup consisting of an insulin, an alpha-glucosidase inhibitor, abiguanide, a dopamine agonist, a DPP-4 inhibitor, a glucagon-likepeptide, a meglitinide, a sodium glucose transporter (SGLT2 or SGLT/2)inhibitor, a sulfonylurea, and a thiazolidinedione.

The second pharmaceutical agents can include exemplary anti-diabeticagents described herein. The second pharmaceutical agents can alsoinclude: alpha-glucosidase inhibitors, e.g., acarbose (Glucor®) andmiglitol (Diastabol®): insulin sensitisers, e.g., thiazolidinediones(TZD), such as pioglitazone (Actos®) and rosiglitazone (Avandia®);agents that reduce glucogenesis, e.g., biguanides, such as metformin(Glucophage®, Stagid®); sulfonylureas (SU) such as carbutamide(Glucidoral®), glibenclamide/glyburide (Daonil®, Euglucan®), glibomuride(Glutril®), gliclazide (Diamicron®), glimepiride (Amarel®), glipizide(Glibenese®), chlorpropamide, and tolazamide: meglinides such asrepaglinide (NovoNorm®): dopamine agonists, such as bromocriptine; DPP-4inhibitors such as alogliptin, linagliptin, saxagliptin, sitagliptin, orvildagliptin; sodium glucose transporter (SGLT2 or SGLT 1/2) inhibitorssuch as dapagliflozin, canagliflozin, empagliflozin, or sotagliflozin.

In some embodiments, the second pharmaceutical agent is a DPP-4inhibitor. In some embodiments the second pharmaceutical agent issitagliptin.

In some embodiments, the second pharmaceutical agent is metformin.

In some embodiments, the prior anti-diabetic treatment, for example,treatment for type 2 diabetes mellitus, does not provide adequatecontrol of or does not adequately control the subject's metabolicdisorder. In some embodiments, the metabolic disorder is type 2 diabetesmellitus. In some embodiments, the prior anti-diabetic treatment doesnot provide adequate control of or does not adequately control thesubject's glycemic parameters, non-glycemic parameters, or both. In someembodiments, the subject is not adequately controlled by the prioranti-diabetic treatment as defined by an HbA_(1c) of not less than about7.5% or by an HbA_(1c) of 7.5% to 10%.

In some embodiments, the prior anti-diabetic treatment is a monotherapy.In some embodiments, the monotherapy includes a pharmaceutical agentselected from the group consisting of an insulin, an alpha-glucosidaseinhibitor, a biguanide, a dopamine agonist, a DPP-4 inhibitor, aglucagon-like peptide, a meglitinide, a sodium glucose transporter(SGLT2 or SGLT1/2) inhibitor, a sulfonylurea, and a thiazolidinedione.In some embodiments, the monotherapy is a pharmaceutical agent includingthe exemplary anti-diabetic agents described herein.

EXAMPLES Example 1 Comparative Effect of Imeglimin, Metformin, andPhenformin on Risks of Lactic Acidosis in Acute Renal Failure (ARF) RatModel

Metformin is associated with risk of lactic acidosis in patients withrenal or/and cardiac failure. The plasma accumulation of metformin inrenal insufficiency is a factor of risk for development of this lacticacidosis. Acute renal failure (ARF) can be performed in rat bygentamicin, which directly produces tubular cell necrosis and may alsocause a fall in renal blood flow.

A study investigating the risk of lactic acidosis induction in rats withacute renal dysfunction after treatment with imeglimin, in comparisonwith biguanides metformin and phenformin was completed.

Renal failure in rats was developed following administration ofgentamicin (200 mg/kg s.c.), followed by randomization: Normal(creatinine <0.6 mg/dL). Moderate (0.6 mg/dL<creatinine <2 mg/dL) andSevere renal failure (creatinine >2 mg/dL). Gentamicin was administeredby subcutaneous route (administration volume: 1 ml/kg weight) once a dayfor 4 days. The creatinine level, correlated with the degree of therenal function failure, was tested for each rat 7 days after the firstinjection of gentamicin. Following administration of gentamicin, renalfailure developed serum creatinine to 1 to 3 mg/dL vs. 0.5 mg/dL normalrat. The creatinine level was determined on the Monarch ChemistrySystems using the IL Test creatinine in rat plasma samples. Thismonochromatic analysis is based on the formation of a red coloredcomplex between creatinine and picric acid under alkaline conditions.

Imeglimin, metformin, or phenformin dissolved in saline was administeredintravenously at a constant rate of 8 ml/h/kg for 180 minutes. The doseswere 100 mg/h/kg (imeglimin and metformin) and 50 mg/h/kg (phenformin)for the Normal group, and 25, 50, 75, 100 mg/h/kg (imeglimin andmetformin) and 25, 50 mg/h/kg (phenformin) for the Moderate and Severegroups.

In normal rats, perfusion of imeglimin at the dose of 100 mg/h/kgsignificantly decreased plasma glucose from 60 minutes (6.5±0.4 vs.7.6±0.4 mmol/L basal t p<0.001). The same effect was observed afterinfusion of phenformin at 50 mg/h/kg or metformin 100 mg/kg/h. But thisdecrease of plasma glucose was more marked in time (180 minutes) 2.9±1mmol/L after phenformin vs. 5.4±0.4 mmol/L after imeglimin and 4±0.7mmol/L after metformin. This hypoglycemic effect was obtained with thesame plasma concentration level of imeglimin (65.16±15.8 μg/ml) andmetformin (84.77+12.27 μg/ml).

In rats with mild or high ARF, the decrease in plasma glucose withimeglimin was significant and time-dependent. But differently frommetformin and phenformin, severe hypoglycemia was not observed withimeglimin. Phenformin and metformin decreased plasma glucose slowly upto 120 minutes; then a sharp fall in plasma glucose appeared, 1.9±1mmol/L for metformin and 2.4±1.1 mmol/L for phenformin.

In normal rats, metformin at 100 mg/h/kg and phenformin at 50 mg/h/kgsignificantly increased lactatemia. Phenformin induced higher productionof lactate than metformin (9.4±2.1 vs. 4.6±0.4 mmol/L). Imeglimin didnot change plasma lactate level. In ARF rats metformin and phenformintreatment significantly increased plasma lactate. This effect on plasmalactate was dose-dependent but also time-dependent. The increase inplasma lactate level induced by metformin was of greater magnitude inthe rats with high ARF than those with mild ARF as defined by creatininelevels as described above. Contrary to these biguanides, imeglimin didnot significantly increase plasma lactate in this ARF rat model.

In ARF rats, metformin and phenformin increased significantly plasma H⁺concentration. This effect appeared 2 hours after perfusion and wasdose-dependent. This pH modification did not seem to correlate withdegree of ARF severity for either compound. Metabolic acidosis signswith imeglimin treatment were not observed.

In ARF rats, phenformin and metformin perfusion significantly decreasedplasma concentration of [HCO₃ ⁻] and this effect was dependent onseverity of ARF. In groups with high creatinine level, [HCO₃ ⁻] fellsignificantly after metformin 100 mg/kg, 11.8±1.1 vs. 22.8±0.8 mmol/L incontrol p<0.001 and after phenformin at 50 mg/kg, 17.7±1.3 vs. 22.8±0.8mmol/L in control p<0.001. Imeglimin also significantly decreased plasma[HCO₃ ⁻] vs. basal period but not vs. control group. This effect wasneither dependent on degree of ARF severity nor compound concentrations.

From 50 mg/kg/h, phenformin induced 85% of mortality, which wasdependent on creatinine plasma concentration. This effect appearedexclusively in the high plasma creatinine group. The main biochemicalcharacteristics of this mortality were hypoglycemia, hyperlactatemia,drop of plasma pH (<7.2) and [HCO₃ ⁻] concentration. These biochemicalalterations are the physiological hallmarks of lactic acidosis.

In the ARF rat model, plasma accumulation of metformin and imeglimin wasobserved. This effect appeared to be dependent on dose but also ondegree of ARF severity. A significant direct relationship between plasmametformin and plasma lactate concentration was observed, r=0.758,p<0.001. Similar significant correlation appeared between plasmametformin and plasma H⁺ concentration, r=0.611, p<0.0156. No significantcorrelation was observed between imeglimin plasma concentration andplasma lactate or H⁺ levels.

Perfusion of metformin or phenformin in this acute renal failure ratmodel induced lactic acidosis. This lethal side effect was characterizedby a dose-dependent increase of plasma lactate and H⁺ and decrease of[HCO₃ ⁻] levels. A significant relationship between lactate level andplasma H⁺ concentration was observed.

Example 2

A Phase 1 clinical study to investigate the pharmacokinetics ofimeglimin in subjects with renal impairment compared to subjects withnormal renal function

An open-label, parallel-group, multi-center, multiple oral dose study toinvestigate the pharmacokinetics of imeglimin in subjects with renalimpairment compared to subjects with normal renal function wascompleted.

In this study, a total of 51 subjects received imeglimin at the dailydose of 1000 mg, administered either as 1000 mg QD (once a day) or 500mg bid (twice a day) during 8 days. Out of 27 subjects with chronicrenal impairment, 9 subjects (5 receiving QD and 4 receiving bidregimen) had mild (creatine clearance (CL_(Crea)) 50-80 mL/min), 12subjects (6 receiving QD and 6 receiving bid regimen) had moderate(CL_(Crea) 30 to <50 mL/min) and 6 subjects (receiving bid regimen) hadsevere renal impairment (CL_(Crea)<30 mL/min). Twenty-four controlsubjects with normal renal function were matched to mild and moderate(10 receiving QD and 8 receiving bid regimen) and to severe (6 receivingbid regimen) renal impaired subjects. Measurement of the urine to plasmaratio of creatinine using 24 hours urine sampling was calculated(CL_(Crea)).

Imeglimin was administered in the morning time during 8 consecutive daysin the group of subjects receiving 1000 mg once a day and in the morningand evening time during 7 consecutive days followed by a morningadministration of 500 mg in the morning time on Day 8 in the group ofsubjects receiving 500 mg twice a day. Morning administrations on Days 1and 8 were performed on a fasted state, after a 10 hours overnightfasting and during 4 hours after imeglimin administration.

Inclusion Criteria: For subjects with normal renal functions:CL_(Crea)>80 mL/min based on calculation using 24-hrs sampling on day−2. For subjects with impaired renal function: CL_(Crea) 50 to 80 mL/minfor subjects with mild renal impairment, 30 to <50 mL/min for subjectswith moderate renal impairment, and <30 mL/min for subjects with severerenal impairment based on calculation using 24-hrs sampling on day −2.

The mean pharmacokinetic parameters of imeglimin obtained on Day 8 oftreatment are presented in Table 1 and Table 2. Pharmacokineticparameters included apparent volume of distribution during the terminalphase following extravascular administration (Vz/F), area under thecurve of the plasma concentration as a function of time (AUC_(0-t)), themaximum observed concentration (C_(max)), the time to maximumconcentration (t_(max)), the plasma half-life (t_(1/2)), the total bodyclearance of drug from plasma following extravascular administration(CL/F), and other parameters.

Median T_(max) was observed at 3.5 to 5 hours post-dose with nodifferences observed over renal function or time. Steady-state ofimeglimin was attained by Day 6 of repeated dosing of 1000 mg QD and 500mg bid, which is consistent with the T_(1/2) (13 to 26 hours).

Renal impairment resulted in accumulation of imeglimin by up to 3.6-foldin subjects with severe renal impairment. The difference in exposurebetween renal impaired subjects and normal subjects was up to 1.5-, 2.3-and 3.6-fold greater in subjects with mild, moderate and severe renalimpairment, respectively on Day 8. Generally, only the increasedexposure in moderate and severe groups compared to the normal renalfunction groups were confirmed statistically. Mean observed plasmaprofiles from Day 1 to Day 8 in subjects with various degrees of renalimpairment, receiving 1000 mg imeglimin QD are shown in FIGS. 1-3. Meanobserved plasma profiles across all days in subjects with normal renalfunction and severe renal impairment, receiving 500 mg imeglimin bid areshown in FIG. 4.

Total oral body clearance and renal clearance decreased with increasedrenal impairment by up to 72% and 74%, respectively, in subjects withsevere renal impairment compared to normal subjects.

A high fraction of dose was excreted in urine for 500 mg bid regimenduring the 12-hour dosing interval, with estimates of 44% to 46% innormal subjects, 43% in mild, 42% in severe and 40% in subjects withmoderate renal impairment.

TABLE 1 Pharmacokinetic parameters in subjects with renal impairmentfollowing oral dose (1000 mg QD) of imeglimin on Day 8 CKD stage 2 (MildCKD Stage 3 Normal renal renal impairment; (Moderate renal Parameterfunction (N = 10) N = 5) impairment; N = 6) AUC_(0-t) (ng · h/mL) 15399(21.2) 20122 (15.7) 29100 (30.4) C_(max) (ng/mL) 1746 (15.9) 2049 (26.3)2573 (21.2) C_(av) (ng/mL) 642 (21.2) 838 (15.7) 1213 (30.4) C_(pre)(ng/mL) 136 (71.4) 181 (25.7) 382 (58.1) C_(min) (ng/mL) 115 (84.4) 178(22.6) 335 (68.4) t_(max) ^(a) (h) 4.00 (3.00, 5.00) 4.00 (3.00, 4.00)5.00 (4.00, 5.00) t_(1/2) (h) 16.4 ^(b) (70.0) 15.0 (74.9) 23.4 (25.9)CL/F (mL/min) 1082 (21.2) 828 (15.7) 573 (30.4) Vz/F (L) 1573 ^(b)(56.5) 1073 (58.8) 1162 (38.5) Geometric mean (CV %) data are presented,N = Number of subjects studied, ^(a)Median (min, max); ^(b) N = 8. QD =quaque die or once a day, AUC = area under the concentration-timeprofile, Cmax = maximum plasma concentration, t½ = eliminationhalf-life, CL/F = apparent oral clearance, Vz/F = apparent volume ofdistribution.

TABLE 2 Pharmacokinetic parameters in subjects with renal impairmentfollowing oral doses (500 mg bid) of imeglimin on Day 8 Part 1 Part 2CKD Stage 2 CKD Stage 3 CKD Stage 4 Normal renal (Mild renal (Moderaterenal Normal renal (Severe renal Parameter function (N = 8) impairment;N = 4) impairment; N = 6) function (N = 6) impairment; N = 5) AUC_(0-τ)7389 (16.8) 11056 (8.10) 17168 (44.4) 6974 (31.0) 24833 (34.1) (ng ·h/mL) C_(max) (ng/mL) 1028 (11.3) 1316 (5.06) 2001 (36.0) 998 (29.7)2857 (29.1) C_(av) (ng/mL) 616 (16.8) 921 (8.10) 1431 (44.4) 581 (31.0)2069 (34.1) C_(pre) (ng/mL) 254 (68.1) 572 (9.45) 996 (48.6) 209 (41.8)1335 (37.4) C_(min) (ng/mL) 202 (50.5) 459 (15.0) 808 (58.3) 169 (24.6)1211 (44.1) t_(max) ^(a) (h) 3.50 (3.00, 5.02) 4.00 (4.00, 5.00) 3.50(2.00, 5.00) 3.75 (3.00, 5.00) 3.50 (3.50, 5.00) t_(1/2) (h) 13.2 (78.8)26.1 (20.0) 21.9 (64.6) 15.0 (53.2) 17.6 (61.8) CL/F (mL/min) 1128(16.8) 754 (8.10) 485 (44.4) 1195 (31.0) 336 (34.1) Vz/F (L) 1290 (63.0)1704 (23.0) 922 (81.8) 1548 (30.1) 511 (102) Geometric mean (CV %) dataare presented, N = Number of subjects studied, ^(a)Median (min, max) bid= bis in die or twice a day, AUC = area under the concentration-timeprofile, Cmax = maximum plasma concentration, t½ = eliminationhalf-life, CL/F = apparent oral clearance, Vz/F = apparent volume ofdistribution.

The urinary excretion parameters of imeglimin in subjects with differingdegrees of renal impairment following QD or bid oral doses of imegliminon day 8 are summarized in Table 3 and Table 4. Parameters measuredinclude amount of unchanged drug excreted in urine as a function of time(Ae_(0-t)), renal clearance (CL_(R)), and the amount of unchanged drugexcreted in urine during one dosing interval (Ae_(0-τ)), and thepercentage of administered dose excreted in urine during one dosinginterval (feτ).

TABLE 3 Urinary excretion parameters in subjects with renal impairment,following oral doses (1000 mg QD) of imeglimin on Day 8 CKD Stage 2 CKDStage 3 Normal renal (Mild renal (Moderate renal function impairment)impairment) Parameter (N = 10) (N = 5) (N = 6) Ae_(0-t) (mg) 460 (22.3)581, 650^(a) (NC) 453 (43.4) Ae_(0-τ) (mg) 386 (27.0) 480, 610^(a) (NC)345 (33.2) fe_(τ) (%) 38.6 (27.0) 48.0, 61.0^(a) (NC) 34.5 (33.2) CL_(R)(mL/min) 418 (30.4) 388, 522^(a) (NC) 197 (17.9) Geometric mean (CV %)data are presented, N = Number of subjects studied, ^(a)N = 2; min, maxpresented, NC = Not calculable.

TABLE 4 Urinary excretion parameters in subjects with renal impairment,following oral doses (500 mg bid) of imeglimin on Day 8 Renal FunctionCKD Stage CKD Stage CKD Stage Normal 2 (Mild 3 (Moderate Normal 4(Severe renal renal renal renal renal function impairment) impairment)function impairment) Parameter (N = 8) (N = 4) (N = 6) (N = 6) (N = 5)Ae_(0-t) (mg) 307 (37.7) 404 (16.4) 328 (22.6) 298 (30.6) 357 (25.5)Ae_(0-τ) (mg) 222 (22.6) 215 (11.5) 199 (29.1) 229 (25.3) 209 (15.6)fe_(τ) (%) 44.4 (22.6)  42.9 (11.5)  39.8 (29.1)  45.9 (25.3)  41.8(15.6)  CL_(R) 501 (30.7) 323 (15.0) 193 (41.0) 548 (11.5) 140 (20.7)(mL/min) Geometric mean (CV %) data are presented, N = Number ofsubjects studied; min, max presented, NC = Not calculable.

Biochemistry and hematological parameters of subjects with normal andmild renal impairment were in most cases normal and only in single casesoutside normal range. All these cases were assessed as not clinicallyrelevant. As expected subjects with moderate and severe renal impairmentshowed values outside normal range for several parameters due to theirunderlying diseases. Urea and creatinine values were outside normalrange in all cases and were assessed as clinically relevant.Hematological parameters were outside normal range in single cases andassessed as not clinically relevant, but were expected due to theirunderlying diseases. In single cases inorganic phosphate, ALT, GLDH, CK,triglyceride, lipase and glucose was increased in subjects with moderateand severe renal impairment and these cases were assessed as clinicallyrelevant. No relevant deviation from normal was observed for sodium,potassium and chloride levels. There was no significant abnormalityobserved in the clinical laboratory parameters. Mean systolic anddiastolic blood pressure values were as expected slightly higher insubjects with severe renal impairment. Vital signs did not show anyclinically relevant changes following the administration of imeglimin.The mean values of PR-intervals did not show any relevant changes duringthe time course of the trial. QRS-, QT intervals and the correctedQTc-intervals according to Bazett and Fridericia did not reveal anyrelevant changes related to the administration of the study drug.

For the evaluation of safety and tolerability of multiple oral doses of1000 mg imeglimin QD (i.e. a total dose of 8000 mg imeglimin) or 500 mgimeglimin BID (i.e. a total dose of 7500 mg imeglimin), laboratory tests(hematology, clinical chemistry, urinalysis), determination of vitalsigns, ECG recordings, questioning of AEs and physical examinations wereperformed. All safety parameters did not show any relevant changesduring the course of the study. The incidence of AEs observed within thecourse of the study was low. Overall 31 out of 51 subjects reported 54treatment emergent AEs. Of these, only 15 were judged as likely relatedto the study drug. The majority (39 AEs) were assessed as unlikelyrelated. Based on these low incidence no clear differences between thedose regimens and between the renal impairment groups can be shown.General safety and tolerability assessment showed a good or very goodtolerability of imeglimin. Overall, the safety and tolerability of atotal daily dose of 1000 mg imeglimin administered either once daily or500 mg imeglimin bid over 8 days is considered as good.

Example 3

A dose-ranging, randomized, double-blind, placebo-controlled,parallel-group, multi-center study of the efficacy and safety of 3 dosesof imeglimin after 24 weeks of treatment in Japanese type 2 diabeticsubjects

In this study, a total of 299 subjects with T2DM received eitherimeglimin at one of the 3 doses (500, 1000 and 1500 mg bid) or placebo.The primary objective of this study was to assess the dose-response ofimeglimin at 3 doses (500, 1000 and 1500 mg bid) compared to placebo inmale and female subjects with T2DM after 24 weeks of treatment, usingglycosylated hemoglobin (HbA1c) as the primary endpoint. InclusionCriteria: subjects have an eGFR of ≥50 mL/min/1.73 m² at screeningand >=45 at pre randomization visit. A total of 299 subjects wererandomized 1:1:1:1 to one of the 4 study arms, with 268 subjectscompleting the study.

The study met its primary endpoint. There was a dose-dependent decreasein placebo-adjusted change in HbA1c vs. baseline that reachedstatistical significance for the 3 doses (−0.52%; −0.94%, and −1.0%;p<0.0001, for 500 mg, 1000 mg and 1500 mg bid, respectively). See Table5 and FIG. 5.

TABLE 5 MMRM analysis of change from baseline in HbA1c (FAS) ImegliminImeglimin Imeglimin Placebo 500 mg bid 1000 mg bid 1500 mg bid FAS N =75 N = 75 N = 73 N = 73 Baseline 7.89 7.94  7.85  7.91  HbA1c (%) LSM0.43 (0.092) −0.09 (0.091) −0.51 (0.093) −0.57 (0.094) difference vsbaseline (SEM) LSM −0.52 (0.128) −0.94 (0.129)  −1.0 (0.130) differencevs placebo (SEM) P value <0.0001 <0.0001 <0.0001

The changes in HbA1c were analyzed depending on the baseline HbA1c<8% or≥8%. The change in HbA1c is similar at the doses of 500 mg bid (−0.47%and −0.58% for baseline <8% and ≥8%, respectively) and 1000 mg bid(−0.93% and −0.90% for baseline <8% and ≥8%, respectively), but islarger at the dose of 1500 mg bid in the patients with higher HbA1c atbaseline (−0.82% and −1.2% for baseline <8% and ≥8%, respectively). SeeFIG. 6.

Percentage of responders was defined as the percentage of subjects whoreached a value of HbA1c≤7% at the end of the 24-week double-blindtreatment period. The analysis was performed using the FAS for subjectswith an HbA1c value greater than 7.0% at baseline.

There was a statistically significant and similar increase in theresponder rate in the 2 top doses of imeglimin (33.3% and 32.9% in the1000 mg bid and 1500 mg bid imeglimin group vs. 8.2% in the placebogroup). During the double blind treatment period, the percentage ofsubjects requiring a rescue therapy due to poor glycemic control washigher in the placebo group (10.7%) compared to other groups with nosubjects requiring rescue therapy in the top dose of imeglimin 1500 mgbid. See FIGS. 7A and 7B.

Decrease in FPG followed the same profile with a similar effect observedat the 2 top doses of 1000 and 1500 mg bid (−24.6 mg/dL or 1.37 mmol/Lp<0.001). See Table 6 and FIG. 8.

TABLE 6 MMRM analysis of change from baseline in FPG (FAS) ImegliminImeglimin Imeglimin Placebo 500 mg bid 1000 mg bid 1500 mg bid FAS N =75 N = 75 N = 73 N = 73 Baseline FPG 160.4 164.5 163.4 164.8 (mg/dL) LSM16.6 (3.33) 8.0 (3.29) −8.0 (3.34) −8.0 (3.39) difference vs baseline(SEM) LSM −8.6 (4.40) −24.6 (4.45) −24.6 (4.46) difference vs placebo(SEM) P value <0.0513 <0.0001 <0.0001

Change from baseline in Glycated Albumin (FAS) is shown in Table 7.

TABLE 7 MMRM analysis of change from baseline in FPG (FAS) ImegliminImeglimin Imeglimin Placebo 500 mg bid 1000 mg bid 1500 mg bid FAS N =75 N = 75 N = 73 N = 73 Baseline Glyc 20.43 (4.05) 21.23 (3.82)  21.05(3.89)  20.06 (4.08)  Alb (%) LSM  1.98 (0.429) −0.35 (0.421) −2.13(0.430) −2.25 (0.431) difference vs baseline (SEM) LSM −2.33 (0.581)−4.11 (0.589) −4.23 (0.588) difference vs placebo (SEM) P value <0.0001<0.0001 <0.0001

The overall incidence of subjects presenting with any adverse event (AE)was similar across the groups ranging from 73% (Imeglimin 1000 mg) to77.3% (Imeglimin 1500 mg). The incidence of subjects presenting withTreatment Emergent (TE) AE ranged from 62.2% (Imeglimin 1000 mg) to73.3% (Imeglimn 1500 mg).

The most common adverse events are from the “Infections andInfestations” and from the “Gastrointestinal disorders” System OrganClass (SOC). Most of the TEAE were of mild intensity.

Only a few number of patients presented TEAE that were considered asrelated to the study drug, with a similar incidence between the placeboand the 2 first doses of imeglimin, 5.3% (imeglimin 500 mg), 5.4%(imeglimin 1000 mg) and 8% (placebo) and an increase at the top dose,24% (imeglimin 1500 mg). This higher incidence in the latter group waspartly driven by an increase in the incidence of TEAE from thegastrointestinal disorder SOC, 14.7% (placebo and imeglimin 500 mg),18.9% (imeglimin 1000 mg) and 32% (imeglimin 1500 mg).

TEAE leading to discontinuation included both hyperglycemia requiringrescue therapy and adverse events of other SOC and were increased in theplacebo (13.3%) versus the imeglimin dose groups (2.7% in 500 mg, 6.8%in the 1000) mg and 6.7% in the 1500 mg). There were no real trendsamong the non-hyperglycemic adverse events leading to withdrawal.

Six serious TEAEs occurred during the course of the study (5.4% in theimeglimin 1000 mg bid, 1.3% in the imeglimin 1500 mg bid and the placebogroups, none in the imeglimin 500 mg bid, respectively). None of themwere related to the study drug. There were no real trends in thenon-related serious TEAE. One serious TEAE led to death in the group of1500 mg (metastatic pancreatic cancer discovered during the course ofthe study).

In conclusion, the study met its primary endpoint showing adose-dependent decrease in placebo-adjusted HbA1c change from baseline,with the dose of 1000 mg and 1500 mg bid exhibiting a similar andmaximal effect.

In a post-hoc analysis, efficacy and safety/tolerability profile wasinvestigated in patients depending on their renal function (CKD1=eGFR≥90 mL/min/1.73 m². CKD2=60≤eGFR <90 mL/min/1.73 m², CKD3A=45≤eGFR<60 mL/min/1.73 m²). 299 patients were randomized. 74% of the patientshad CKD2, 14% had CKD1, and 12% CKD3A, respectively. The primaryendpoint was met with a statistically significant dose-dependent placebosubtracted decrease in HbA1c at the 3 doses with the 2 top doses of1,000 and 1,500 mg bid reaching an HbA1c decrease of −0.94% and −100%respectively (Table 5). Imeglimin demonstrated an improvement in HbA1clowering as compared to placebo. There were no major differences in theincidence of AE, SAE or AE leading to treatment discontinuation. No SAEor AE leading to discontinuation were observed in CKD3a subgroup.

In subjects with T2D and Stage 2 CKD reductions in HbA1c versus placebowere −0.60, −1.03, and −1.11 for 500 mg BID, 1000 mg BID, and 1500) mgBID imeglimin, respectively at 24 weeks. In addition, subjects with T2Dand Stage 3a CKD reductions in HbA1c versus placebo were −0.54, −0.44,and −1.07 for 500 mg BID, 1000 mg BID, and 1500 mg BID imeglimin,respectively at 24 weeks (Table 8). Unlike the reduced HbA1c efficacyobserved with SGLT2i in CKD, the preponderance of these data suggestgreater HbA1c efficacy with imeglimin in subjects with CKD isindependent of renal function and does not decline with CKD.

Mean Change in HbA1c (%) from baseline to Week 24 (end of treatment) forImeglimin in Subjects broken down by eGFR category are listed in Table8.

TABLE 8 eGFR Sub- Imeglimin Category Placebo 500 mg BID 1000 mg BID 1500mg BID Normal eGFR N  9  9 9 14 (eGFR > 90 Week 24 LS Mean (SEM) 0.05(0.213)  0.04 (0.221)  −0.8 (0.213) −0.42 (0.175) mL/min/ LSM 95% CI−0.38, 0.48 −0.41, 0.48 −1.23, −0.37 −0.77, −0.06 1.73 m²) LSMDifference vs. −0.01 (0.290) −0.85 (0.283) −0.47 (0.260) Placebo (SEM)LSM Difference vs. −0.60, 0.58 −1.43, −0.28 −0.99, 0.06  Placebo 95% CICKD Stage 2 N 55 56 57  51 (eGFR = 60-90 Week 24 LS Mean (SEM) 0.52(0.112) −0.08 (0.109) −0.51 (0.110) −0.58 (0.117) mL/min/ LSM 95% CI 0.30, 0.74 −0.29, 0.14 −0.72, −0.29 −0.81, −0.35 1.73 m²) LSMDifference vs. −0.60 (0.154) −1.03 (0.155) −1.11 (0.160) Placebo (SEM)LSM Difference vs.  −0.91, −0.30 −1.33, −0.72 −1.42, −0.79 Placebo 95%CI CKD Stage 3a N 11 10 7  8 (eGFR < 60 Week 24 LS Mean (SEM) 0.22(0.239) −0.32 (0.240) −0.22 (0.282) −0.86 (0.265) mL/min/ LSM 95% CI−0.27, 0.71 −0.81, 0.17 −0.80, 0.36  −1.40, −0.31 1.73 m²) LSMDifference vs. −0.54 (0.336) −0.44 (0.368) −1.07 (0.353) Placebo (SEM)LSM Difference vs. −1.23, 0.15 −1.19, 0.32  −1.80, −0.35 Placebo 95% CIeGFR = estimated glomerular filtration rate; LSM = least squares mean;SEM = standard error of means; 95% CI = 95% confidence interval

Fasting plasma glucose (FPG) decreased in a consistent manner insubjects with CKD Stages 2 and 3a (Table 9). Unlike reduced FPG efficacyin CKD observed with SGLT2i, the preponderance of these data suggestsgreater FPG efficacy with imeglimin in subjects with CKD compared tosubjects with normal renal function.

Mean Change in FPG (mg/dL) from baseline to Week 24 (end of treatment)for Imeglimin in Subjects broken down by eGFR category are listed inTable 9.

TABLE 9 eGFR Sub- Imeglimin Category Placebo 500 mg BID 1000 mg BID 1500mg BID Normal eGFR N  9  9 9 14 (eGFR > 90) Week 24 LS Mean (SEM) 1.5(8.80) 15.9 (9.26) −26.6 (8.84) 6.6 (7.44) mL/min/ LSM 95% CI −16.3,19.2 −2.7, 34.6 −44.4, −8.8  −8.4, 21.6 1.73 m² LSM Difference vs. 14.5(10.97) −28.1 (10.68) 5.1 (9.94) Placebo (SEM) LSM Difference vs. −7.8,36.8 −49.8, −6.4 −15.1, 25.3 Placebo 95% CI CKD Stage 2 N 55 56 57  51(eGFR = 60-90 Week 24 LS Mean (SEM) 20.0 (4.02)  5.8 (3.93) −6.5 (3.95)−12.9 (4.21) mL/min/ LSM 95% CI  12.1, 28.0 −1.9, 13.6 −14.3, 1.3 −21.2, −4.6 1.73 m²) LSM Difference vs. −14.2 (5.30) −26.5 (5.34) −33.0(5.50) Placebo (SEM) LSM Difference vs. −24.7, −3.8   −37.0, −16.0 −43.8, −22.1 Placebo 95% CI CKD Stage 3a N 11 10 7  8 (eGFR < 60 Week24 LS Mean (SEM) 8.4 (5.68) 1.7 (6.03) −2.8 (6.30) −12.2 (6.57) mL/min/LSM 95% CI  −3.1, 19.9 −10.6, 13.9  −15.7, 10.1 −25.6, 1.2  1.73 m²) LSMDifference vs. −6.7 (7.77) −11.2 (8.07) −20.6 (7.71) Placebo (SEM) LSMDifference vs. −22.6, 9.1  −27.7, 5.3  −36.4, −4.8 Placebo 95% CI eGFR =estimated glomerular filtration rate; LSM = least squares mean; SEM =standard error of means; 95% CI 95% confidence interval

Example 4 A Population Pharmacokinetic (popPK) Model Study for Imegliminin Subjects with Type 2 Diabetes Mellitus (T2DM) and in Healthy Subjects

A population pharmacokinetic (popPK) model for imeglimin monotherapyafter repeated oral administration in subjects with type 2 diabetesmellitus (T2DM) and in healthy subjects was developed to support thedose adjustment needed in subjects with chronic kidney disease (CKD).The popPK model was built using PK datasets from a Phase 1 study inhealthy Japanese and Caucasian subjects, a Phase 1 study in renallyimpaired otherwise healthy Caucasian subjects, Phase 2a studies, andPhase 2b studies. The popPK model was used to simulate plasma exposureat steady-state following different dosing regimens and according to thedegree of renal impairment. The simulations were performed to supportthe selection of dosing regimen in chronic kidney disease CKD2 (mildrenal impairment), CKD3 (moderate renal impairment, including 3A and 3B)and CKD4 (severe renal impairment) subjects. Dosing regimens weredefined on the basis of the efficacious doses observed in T2DM subjects.Simulations and tolerability and safety data obtained in the Phase 2bstudies support the following dosage adjustment in CKD subjects: 1000mg/1500 mg bid in subjects with normal renal function and CKD2; 1000 mgbid in CKD3 subjects; 750 mg QD in CKD4 subjects, as shown in FIG. 9.

In addition, predicted daily steady-state exposures (AUC_(24,ss)) fordoses of 500 mg BID. 1500 mg QD, and 1000 mg BID in T2DM subjects withCKD stage 3B or 4 in a Phase 1b study were estimated using parametersfrom the population PK model: the mean AUC_(24,ss) values and standarddeviations are shown in FIG. 10. For reference, the mean AUC_(24,ss) andstandard deviation from a Phase 2b clinical study is also included inFIG. 10; the mean AUC_(24,ss) in the 1500 mg BID treatment arm in thatstudy was 36.5 μg·hr/mL (the AUC_(24,ss) range was 10.1 to 169.3 μghr/mL). At each of the three dose levels, significant overlap inexposure between T2DM subjects with CKD3B and T2DM subjects with CKD4was predicted as evidenced by the overlap of standard deviation barsbetween CKD3B and CKD4 subjects at each dose level.

The dosing regimens from the simulations can be used for treatingdiabetic subjects with various stages of CKD.

Example 5 An Open Label, Parallel Arm Study to Assess the Safety,Tolerability, and Pharmacokinetics of Imeglimin in Subjects with Type 2Diabetes Mellitus (T2DM) and Moderate to Severe Chronic Kidney Disease(CKD)

This Phase 1b study is to assess the safety, tolerability andpharmacokinetics (PK) of imeglimin in subjects with T2DM and CKD stage3B or 4.

The doses included in this study are 500 mg twice daily (BID), 1500 mgonce daily (QD), and 1000 mg twice daily (BID) given to subjects withtype 2 diabetes and CKD stage 3B or 4 as reflected in average eGFR,calculated using the MDRD equation, of between 15 and 29 (CKD4) or 30and 44 (CKD3B) ml/min/1.73 m², inclusive, for a treatment period of 28days. Subjects will be randomly allocated to receive one of threetreatments or placebo.

Inclusion Criteria

-   1) Male or female subjects who are >40 and <75 years of age.-   2) Subjects diagnosed with T2DM at least 2 years prior to Screening    and receiving any background regimen of approved anti-hyperglycemic    medications, with the exception of metformin, at stable doses for at    least 12 weeks prior to the start of screening. Subjects receiving    only nonpharmacological diabetes management (diet and exercise) may    also be included.-   3) Subjects with type 2 diabetes and CKD stage 3B or 4 as reflected    in average eGFR, based on two eGFR values taken during the Screening    period at a minimum of 3 days apart, calculated using the MDRD    equation of between 15 and 29 (CKD4) or 30 and 44 (CKD3B)    ml/min/1.73 m², inclusive.-   4) Subjects should be receiving standard of care treatment for their    diabetic nephropathy with an angiotensin converting enzyme inhibitor    (ACEi) and/or an angiotensin 11 receptor blocker (ARB) at a stable,    therapeutically appropriate dose for at least 12 weeks prior to the    start of Screening. Doses which are below the minimally acceptable    doses are acceptable if stable for 12 weeks prior to Screening as    per prescribing information. Subjects with intolerance to ACEi or    ARB therapy documented in the medical history may be enrolled.-   5) HbA1c between 6.8% and 12.0%, inclusive, at Screening.

Primary Outcome Measures

Area under the concentration-time curve from time 0 to 12 hourspost-dose (AUC₀₋₁₂), maximum concentration (C_(max)), and time tomaximum concentration (t_(max)) on Day 15 of each of the three dosingarms can be calculated. Changes from baseline in fasting plasma glucose(FPG), glycated albumin, and glycosylated hemoglobin (HbA1c) can also bemeasured.

Safety can be evaluated by assessment of clinical laboratory tests,physical examinations, vital signs measurements, and ECG readings atvarious time points during the study, and by the documentation of AEs.

AE verbatim text will be coded and classified by body system andpreferred (coded) term using the MedDRA system organ class (SOC) andpreferred term (PT).

The incidence of treatment-emergent adverse events (TEAE) will besummarized by treatment. The TEAE analyses will include the followingsummaries:

-   1) Adverse event overview for subjects with at least 1 AE in any of    the following categories: AEs, SAEs, AEs with outcome of death, and    AEs leading to discontinuation of investigational product;-   2) All TEAEs by SOC and PT:-   3) All TEAEs by preferred term and investigator's causality    assessment (related vs. not related) and maximum intensity;-   4) All SAEs by SOC and PT:-   5) TEAEs leading to treatment discontinuation;-   6) All Adverse Events of Special Interests (AESIs).

Clinical chemistry, hematology, and urinalysis values will be listed foreach subject and flagged high or low relative to the normal range whereappropriate. All continuous laboratory parameters will be summarizeddescriptively by absolute value at each visit by treatment group,together with the corresponding changes from baseline. Descriptivesummary statistics will be created by treatment and visit.

Renal function is a safety parameter in this study assessed by eGFRderived from serum creatinine using the MDRD equation. Descriptivesummary will be provided for eGFR, serum creatinine, urinary albumin,creatinine and the calculated urinary albumin to creatinine ratio (ACR)from a spot urine sample by treatment and visit.

Plasma lactate will be summarized descriptively by absolute value ateach visit by treatment group, together with the corresponding changesfrom baseline.

Vital signs and physical examination will be summarized descriptively bytreatment and visit. Details will be provided in the SAP.

Pharmacokinetics (PK) data can be descriptively summarized by treatmentgroup. PK parameters will be determined using noncompartmental methods.Some PK summaries can also be displayed by baseline CKD stage groups.Steady-state can be evaluated using the trough concentration data.

The descriptive Pharmacodynamics (PD) summaries can be presented forabsolute value by treatment group, together with the correspondingchanges from baseline for FPG, glycated albumin and HbA1c.

Following completion of the above Phase 1b study to assess the safety,tolerability and pharmacokinetics (PK) of imeglimin in subjects withT2DM and CKD stage 3B or 4, the study data support the safety andtolerability of imeglimin in subjects having CKD stage 3B or 4.

Patients with CKD have other comorbidities that cause their CKD andcontribute to the risk of cardiovascular events and death. Patients withmoderate to severe CKD have an increased prevalence of thesecomorbidities, as evidenced by the subjects with CKD stages 3B and 4enrolled in this study, of whom there were 100% with T2DM, 100% withhypertension, 41% with cardiac disorders. 63% with anemia. 41% withendocrine disorders, and 53% with eye disorders (Table 10). Despite thesignificant underlying conditions in this patient population imegliminwas well tolerated as CKD severity increased (up to stage 4) with noincidence of serious adverse events, no lactic acidosis, and no cases ofconfirmed plasma lactate elevations. Overall treatment-emergent adverseevents (TEAE), whether or not related to study drug, were all mild ormoderate and similar in frequency for imeglimin-treated subjectscompared to placebo for both CKD stages 3B and 4 (Table 11). TEAEsrelated to study drug were almost all mild and similar in frequencybetween imeglimin and placebo for CKD stages 3B and 4. Gastrointestinaldisorders, the most common adverse events, were similar forimeglimin-treated and placebo-treated subjects. These data suggestbetter gastrointestinal tolerance compared to placebo than is reportedfor metformin, and without an increased risk of lactic acidosis.

Extensive blood sampling for pharmacokinetic analysis occurred on Day15. After the morning dose of imeglimin on Day 15, maximum observedconcentrations (Cmax) increased in a dose-dependent manner (FIG. 11).The area under the concentration-time (AUC) profiles (AUC) were similarbetween the 500 mg BID and 1500 mg BID treatment group but did increasein the 1000 mg BID treatment group (FIG. 12). The AUC was increased inthe T2DM with CKD stage 4 compared to CKD3B in the 1500 mg QD and 1000mg BID treatment groups (FIG. 12). This is likely due to the reducedrenal filtration rate in these subjects. Despite the significantincrease in systemic exposure (AUC) in the CKD stage 4 groupadministered with 1000 mg BID imeglimin, the incidence of adverse eventswas not increased compared to other treatment groups (Table 11).Surprisingly, the rate of gastrointestinal events trends at a lower ratein the 1000 mg BID treatment group compared to the 1500 mg QD treatmentgroup despite the higher systemic exposures to imeglimin in the former(Table 11).

TABLE 10 Pre-existing Medical History by System Organ Class andPreferred Term by Treatment in Subjects with Type 2 Diabetes Mellitus(T2DM) and Moderate to Severe Chronic Kidney Disease (CKD) Enrolled in a28 Day Study with Imeglimin Imeglimin Imeglimin Imeglimin ImegliminOverall Placebo 500 mg BID 1500 mg QD 1000 mg BID Total Total (N = 11)(N = 13) (N = 12) (N = 13) (N = 38) (N = 49) Subjects with any medical11 (100%) 13 (100%) 12 (100%) 13 (100%)  38 (100%)  49 (100%) historyType 2 Diabetes Mellitus 11 (100%) 13 (100%) 12 (100%) 13 (100%)  38(100%)  49 (100%) Hyperkalaemia 6 (55%) 6 (46%) 3 (25%) 5 (39%) 14 (37%)20 (41%) Hypertension 11 (100%) 13 (100%) 12 (100%) 13 (100%)  38 (100%) 49 (100%) Cardiac Disorders 2 (18%) 6 (46%) 8 (67%) 4 (31%) 18 (47%) 20(41%) Gastrointestinal Disorders 10 (91%)  10 77%) 8 (67%) 9 (69%) 27(71%) 37 (76%) Nervous System Disorders 8 (73%) 9 (69%) 9 (75%) 10(77%)  28 (74%) 36 (74%) Musculoskeletal and 9 (82%) 10 (77%)  7 (58%) 8(62%) 25 (66%) 34 (69%) Connective tissue Disorders Blood and lymphaticsystem 6 (55%) 8 (62%) 6 (50%) 11 (85%)  25 (66%) 31 (63%) disorders(anemia) Eye disorders 10 (91%)  7 (54%) 4 (33%) 5 (39%) 16 (42%) 26(53%) Endocrine Disorders 2 (18%) 6 (46%) 8 (67%) 4 (31%) 18 (47%) 20(41%)

TABLE 11 Treatment-Emergent Adverse Events in Subjects with Type 2Diabetes Mellitus (T2DM) and Moderate to Severe Chronic Kidney Disease(CKD) Enrolled in a 28 Day Study with Imeglimin Imeglimin ImegliminImeglimin Imeglimin Placebo 500 mg BID 1500 mg QD 1000 mg BID TotalCKD3b CKD4 CKD3b CKD4 CKD3b CKD4 CKD3b CKD4 CKD3b CKD4 (n = 6) (n = 5) n= 8 (n = 5) (n = 17) (n = 5) (n = 6) (n = 7) (n = 21) (n = 17) Subjectswith any TEAE 4 (67%) 2 (40%) 2 (25%) 1 (20%) 4 (57%) 3 (60%) 4 (67%) 4(57%) 10 (48%)  8 (47%) (n, %) Subjects with any TEAE by maximumseverity Grade 1 - Mild 2 (33%) 1 (20%) 1 (13%) 0 3 (43%) 3 (60%) 2(33%) 2 (29%) 6 (29%) 5 (29%) Grade 2 - Moderate 2 (33%) 1 (20%) 1 (13%)1 (20%) 1 (14%) 0 2 (33%) 2 (29%) 4 (19%) 3 (18%) Grade 3 - Severe 0 0 00 0 0 0 0 0 0 Grade 4 - Life- 0 0 0 0 0 0 0 0 0 0 threatening Grade 5 -Death 0 0 0 0 0 0 0 0 0 0 Gastrointestinal 3 (50%) 1 (20%) 1 (13%) 0 3(43%) 2 (40%) 1 (17%) 2 (29%) 5 (24%) 4 (24%) disorders Subjects withany 2 (33%) 1 (20%) 0 0 1 (14%) 2 (40%) 2 (33%) 1 (14%) 3 (14%) 3 (18%)study drug related TEAE Grade 1 - Mild 2 (33%) 1 (20%) 0 0 1 (14%) 2(40%) 1 (17%) 1 (14%) 2 (10%) 3 (18%) Grade 2 - Moderate 0 0 0 0 0 0 1(17%) 0 1 (5%)  0 Grade 3 - Severe 0 0 0 0 0 0 0 0 0 0 Grade 4 - Life- 00 0 0 0 0 0 0 0 0 threatening Grade 5 - Death 0 0 0 0 0 0 0 0 0 0

Example 6 A 24-Week, Phase IIb, Dose-Ranging, Randomized, Double-blind.Placebo-controlled, Parallel-group Safety and Efficacy Study in Subjectswith T2DM

The five parallel groups included 4 groups of imeglimin doses (500,1000, 1500, or 2000 mg twice daily) and 1 placebo group. The primaryendpoint was to assess the dose-response in T2D subjects, using changein HbA1c from baseline to week 24 as the primary evaluation criterion.Subjects could be either treatment naïve or treated with any oralantidiabetic monotherapy and were to have an eGFR of ≥50 mL/min/1.73 m².A total of 382 subjects were randomized 1:1:1:1:1 to one of the 5 studyarms, with 315 subjects completing the study. In a post-hoc analysis ofsubjects with T2D and stage 2 and 3a CKD [eGFR of <90 mL/min/1.73 m²(n=211)], imeglimin demonstrated an improvement in HbA1c lowering ascompared to placebo.

Mean Change in HbA1c (%) from baseline to Week 24 (end of treatment) forImeglimin in Subjects with T2D and Stage 2 and 3a CKD are listed inTable 12 below

TABLE 12 Mean (SD) HbA1c Change Treatment from Baseline Placebo (n = 41)0.161 (0.878) 500 mg BID (n = 44) 0.007 (1.06) 1000 mg BID (n = 43)−0.072 (0.996) 1500 mg BID (n = 41) −0.502 (0.855) 2000 mg BID (n = 42)−0.193 (1.06)

Example 7 A 24-week Phase III, Randomized, Double-blind,Placebo-controlled, Monotherapy Study to Assess the Efficacy, Safety andTolerability of Imeglimin Administered Orally in Japanese Patients withtype 2 Diabetes (T2DM)

A total of 213 subjects were randomized in a 1:1 ratio to receive eitherimeglimin (1000 mg BID) or placebo BID for 24 weeks, with 194 subjectscompleting the study without Investigational Medicinal Product (IMP)discontinuation. The primary objective of this study was to determinethe change in HbA1c from baseline after 24 weeks of imeglimin treatmentcompared to placebo. Secondary endpoints of the trial included fastingplasma glucose along with other standard glycemic and non-glycemicparameters. Subjects were to have an eGFR of ≥50 mL/min/1.73 m² atScreening and ≥45 mL/min/1.73 m² at Pre-randomization. In apre-specified analysis of subjects with T2D and stage 2 and 3a CKD [eGFRof <90 mL/min/1.73 m² (n=178)], imeglimin demonstrated an improvement inA1C lowering as compared to placebo.

In this study, HbA1c reduction was evaluated at Week 24. In subjectswith normal eGFR (>90 mL/min/1.73 m²) treated with imeglimin 1000 mgBID, the placebo corrected HbA1c reduction was −0.59%. The placebocorrected HbA1c reduction was larger in subjects with CKD: −0.96% and−0.70% for stage 2 CKD and stage 3a CKD, respectively. Similar to theresults from Example 3, the preponderance of these data suggest greaterHbA1c efficacy with imeglimin in subjects with CKD is independent ofrenal function and does not decline with CKD.

Mean Change in HbA1c (%) from baseline to Week 24 (end of treatment) forImeglimin in Subjects broken down by eGFR category are listed in Table13 below.

TABLE 13 Imeglimin eGFR Sub- 1000 mg Category Placebo BID Normal eGFR N 5 11 (eGFR > 90 Week 24 LS Mean (SE) 0.26 (0.27) −0.33 (0.20)mL/min/1.73 m²) LSM 95% CI −0.32, 0.84 −0.77, 0.10  LSM Difference vs.−0.59 (0.32) Placebo (SE) LSM Difference vs. −1.30, 0.11  Placebo 95% CICKD Stage 2 N 75 66 (eGFR = 60-90 Week 24 LS Mean (SE) 0.14 (0.08) −0.82(0.08) mL/min/1.73 m²) LSM 95% CI −0.02, 0.31 −0.99, −0.65 LSMDifference vs. −0.96 (0.11) Placebo LSM Difference vs. −1.17, −0.75Placebo 95% CI CKD Stage 3a N 16 21 (eGFR < 60 Week 24 LS Mean (SE) 0.04(0.14) −0.66 (0.13) mL/min/1.73 m²) LSM 95% CI −0.24, 0.32 −0.93, −0.40LSM Difference vs. −0.70 (0.19) Placebo LSM Difference vs. −1.08, −0.32Placebo 95% CI eGFR = estimated glomerular filtration rate; LSM = leastsquares mean; SE = standard error; 95% CI = 95% confidence interval

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents, patent applications, and other publications cited hereinare fully incorporated by reference herein in their entirety.

1. A method of treating prediabetes or type 1 or type 2 diabetesmellitus comprising administering to a subject in need thereof aneffective amount of imeglimin, wherein the subject has chronic kidneydisease. 2-4. (canceled)
 5. The method of claim 1, wherein the subjecthas moderate renal impairment or stage 3 chronic kidney disease. 6.(canceled)
 7. (canceled)
 8. The method of claim 1, wherein the subjecthas severe renal impairment or stage 4 chronic kidney disease. 9.(canceled)
 10. The method of claim 5, wherein the subject has anestimated glomerular filtration rate (eGFR) of between about 30ml/min/1.73 m² and about 59 ml/min/1.73 m².
 11. (canceled) 12.(canceled)
 13. The method of claim 8, wherein the subject has anestimated glomerular filtration rate (eGFR) of between about 15ml/min/1.73 m² and about 29 ml/min/1.73 m².
 14. (canceled) 15.(canceled)
 16. The method of claim 1, wherein the subject has one ormore pre-existing medical conditions.
 17. The method of claim 16,wherein the one or more pre-existing medical condition is not chronickidney disease and is selected from hyperkalaemia, hypertension, cardiacdisorders, gastrointestinal disorders, nervous system disorders, bloodand lymphatic system disorders (such as anemia), eye disorders,endocrine disorders, or combinations thereof.
 18. (canceled) 19.(canceled)
 20. The method of claim 16, wherein the imeglimin-treatedsubject's one or more pre-existing medical conditions do not worsen inseverity or symptomatology following treatment with imeglimin. 21-23.(canceled)
 24. The method of claim 16, wherein the one or morepre-existing medical condition is a gastrointestinal disorder. 25.(canceled)
 26. (canceled)
 27. The method of claim 1, wherein theimeglimin-treated subject does not experience an increase in frequencyof lactic acidosis compared to before the subject initiated imeglimintreatment. 28-33. (canceled)
 34. The method of claim 1, wherein theamount of imeglimin is about 500 mg to about 3000 mg per day. 35-39.(canceled)
 40. The method of claim 34, wherein imeglimin is administeredabout 500 mg twice a day, about 1000 mg twice a day, or about 1500 mgonce a day. 41-43. (canceled)
 44. The method of claim 1, whereinimeglimin is administered in the form a hydrochloride salt.
 45. Themethod of claim 1, wherein the subject experiences a placebo-subtracteddecrease in glycosylated hemoglobin (HbA1c) percentage of between about−0.5% and about −1.2% over a treatment period. 46-54. (canceled)
 55. Amethod of treating prediabetes or type 1 or type 2 diabetes mellituscomprising administering to a subject in need thereof an effectiveamount of imeglimin, wherein imeglimin is administered with a secondpharmaceutical agent and wherein the subject has chronic kidney disease.56-73. (canceled)
 74. A method of improving glycemic control in asubject having prediabetes or type 1 or type 2 diabetes comprisingadministering to the subject in need thereof an effective amount ofimeglimin, wherein the subject has chronic kidney disease.
 75. Themethod of claim 74, wherein the subject has moderate renal impairment orstage 3 chronic kidney disease.
 76. The method of claim 74, wherein thesubject has severe renal impairment or stage 4 chronic kidney disease.77-86. (canceled)
 87. The method of claim 74, wherein the subjectexperiences a placebo-subtracted decrease in glycosylated hemoglobin(HbA1c) percentage of between about −0.5% and about −1.2% over atreatment period.
 88. A method of treating a subject having prediabetesor type 1 or type 2 diabetes and chronic kidney disease comprising a)determining the subject's renal impairment based on the subject'sestimated glomerular filtration rate (eGFR); and b) administering to thesubject imeglimin about 500 mg twice a day, about 1500 mg once a day, orabout 1000 mg twice a day if the subject has moderate or severe renalimpairment.